Effect of Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor on Chemotherapy-Induced Myelosuppression

Abstract

An increase in the dose of chemotherapy enhances the response of many experimental and clinical cancers, but the extent of dose escalation is often limited by myelosuppression. In preliminary trials, recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) has augmented leukocyte numbers and function, but the optimal dose is not established. We treated 16 adults who had inoperable or metastatic sarcomas with escalating doses of rhGM-CSF before and immediately after a first cycle of chemotherapy (cycle 1) to assess hematologic response and toxicity. A second cycle of chemotherapy (cycle 2) was given without rhGM-CSF. RhGM-CSF was tolerated well at doses of 4 to 32 micrograms per kilogram of body weight per day. At 64 micrograms per kilogram per day, edema and thrombi around a central venous catheter developed in two of four patients. Leukocyte and granulocyte counts increased significantly during the rhGM-CSF infusion. Neutropenia after cycle 1 was significantly less severe and shorter in duration than after cycle 2 (P less than 0.01). Mean total leukocyte and platelet nadirs were 1.0 and 101 x 10(9) per liter for cycle 1 and 0.45 and 44 x 10(9) per liter for cycle 2 (P less than 0.01), and the median intervals from day 1 of chemotherapy to neutrophil recovery (greater than 0.500 x 10(9) per liter) were 15 and 19 days, respectively (P less than 0.01). The duration of neutropenia was 3.5 days with cycle 1 and 7.4 days with cycle 2 (P less than 0.01). We conclude that rhGM-CSF is tolerated well at doses up to 32 micrograms per kilogram per day and is biologically active in leukopenic patients. It merits further evaluation for the prevention of morbidity from chemotherapy.

Application of cytokine intervention for improved radio-antibody dose delivery

“…Further support for a need to adjust the dose scheduling of cytokine intervention comes from other studies in which the utility of bone marrow transplant (BMT) to reduce RAIT-induced myelosuppression was evaluated. We found that the optimal window of efficacy varied from 2 to 3 days post-RAIT when using a 90 Y fragment, from 4 to 5 days for a 90 Y-IgG and from 6 to 8 days for an 131 I-IgG (Blumenthal et al, 1995a;Antman et al, 1988).…”

Granulocyte-macrophage colony stimulating factor (GM-CSF) after high-dose melphalan in patients with advanced colon cancer

“…A randomised study would be necessary to confirm the relative benefits of the use of haemopoietic growth factors and ABMR following HDM. Effects of GM-CSF on platelet production have been seen previously in patients with myelodysplasia (Vadhan-Raj et al, 1988) and after chemotherapy (Antman et al, 1988) and could be anticipated from in vitro bone marrow culture experiments (Metcalf, 1985).…”

“…Several trials have shown that haemopoietic growth factors can reduce the myelotoxicity of chemotherapy (Bronchud et al, 1987;Antman et al, 1988;Morstyn et al, 1988) and we therefore decided to combine high-dose melphalan with GM-CSF for patients with metastatic colorectal carcinoma in the hope that we could obtain similar response rates to those of Leff et al…”

GM-CSF-transduced B16 melanoma cells are highly susceptible to lysis by normal murine macrophages and poorly tumorigenic in immune-compromised mice

“…It is secreted by activated T cells, endothelial cells, fibroblasts, and macrophages [4]. Due to its effect on hematopoietic cells, GM-CSF has been used to counter myelosuppression induced by high-dose chemotherapy, to bolster host defenses in immunocompromised states, and to accelerate recovery after bone marrow transplantation [5][6][7][8].…”